HAMLET: Functional Properties and Therapeutic Potential

James Ho CS; Anna Rydström; Maria Trulsson; Johannes Bålfors; Petter Storm; Manoj Puthia; Aftab Nadeem; Catharina Svanborg

Disclosures

Future Oncol. 2012;8(10):1301-1313. 

In This Article

Abstract and Introduction

Abstract

Human α–lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein–lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.

Introduction

New, targeted cancer therapies are starting to appear but the lack of specificity for tumor cells remains a significant problem.[1,2] Few molecules destroy cancer cells without harming healthy tissues and the side effects of current cancer drugs are so common that they have become accepted as a necessary element of tumor therapy. Diverse technologies and conceptual approaches have therefore been explored to identify how tumor cells differ from healthy cells, to understand the mechanisms of tumorigenesis and to explore new targets for more tumor-selective therapies.[3–8] Promising candidates inducing tumor-specific cell death include chicken anemia virus-derived apoptosis-inducing protein (apoptin), adenovirus early region 4 open reading frame (E4orf4), parvovirus-H1-derived NS1, human cytokines MDA-7 and TNF-related apoptosis-inducing ligand.[3,7]

Human α-lactalbumin made lethal to tumor cells (HAMLET) is a complex of partially unfolded α-lactalbumin and oleic acid that kills tumor cells and immature cells, but not fully differentiated healthy cells.[9] The activity of HAMLET was discovered by serendipity while using human milk fractions to block bacterial adherence to lung carcinoma cells. One milk fraction killed the tumor cells and the molecular complex responsible for this effect was identified as a folding variant of α-lactalbumin bound to oleic acid.[10] Early in vitro experiments showed that HAMLET has broad antitumor activity with a high degree of tumor selectivity.[9] This is reviewed elsewhere.[11] Recently, HAMLET's broad antitumor activity has been explained by specific effects of oncogenic transformation and by targets in the metabolic machinery in tumor cells.[12] Furthermore, molecular and cellular targets have been extensively characterized.

The tumoricidal activity of HAMLET and the relative selectivity for tumor tissue is maintained in vivo, which has been shown in two human studies and several animal models. HAMLET treatment delayed the progression of human glioblastoma xenografts in nude rats and increased survival, triggering apoptotic changes in the tumor without evidence of cell death in healthy brain tissue.[13] In a placebo-controlled clinical study, topical administration of HAMLET removed skin papillomas without side effects[14] and in patients with bladder cancer, local instillations of HAMLET killed tumor cells but not healthy cells in surrounding tissues. In addition, HAMLET triggered rapid shedding of tumor cells into the urine and caused a reduction in tumor size in patients with bladder cancer.[15]

This review summarizes studies on the structure, function and therapeutic effects of the HAMLET complex and discusses HAMLET's potential as a tool in the development of new cancer therapeutics.

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